Gene expression profiling to predict the risk of locoregional recurrence in breast cancer: a pooled analysis

Abstract

The 70-gene signature (MammaPrint) has been developed to predict the risk of distant metastases in breast cancer and select those patients who may benefit from adjuvant treatment. Given the strong association between locoregional and distant recurrence, we hypothesize that the 70-gene signature will also be able to predict the risk of locoregional recurrence (LRR). 1,053 breast cancer patients primarily treated with breast-conserving treatment or mastectomy at the Netherlands Cancer Institute between 1984 and 2006 were included. Adjuvant treatment consisted of radiotherapy, chemotherapy, and/or endocrine therapy as indicated by guidelines used at the time. All patients were included in various 70-gene signature validation studies. After a median follow-up of 8.96 years with 87 LRRs, patients with a high-risk 70-gene signature (n = 492) had an LRR risk of 12.6% (95% CI 9.7-15.8) at 10 years, compared to 6.1% (95% CI 4.1-8.5) for low-risk patients (n = 561; P < 0.001). Adjusting the 70-gene signature in a competing risk model for the clinicopathological factors such as age, tumour size, grade, hormone receptor status, LVI, axillary lymph node involvement, surgical treatment, endocrine treatment, and chemotherapy resulted in a multivariable HR of 1.73 (95% CI 1.02-2.93; P = 0.042). Adding the signature to the model based on clinicopathological factors improved the discrimination, albeit non-significantly [C-index through 10 years changed from 0.731 (95% CI 0.682-0.782) to 0.741 (95% CI 0.693-0.790)]. Calibration of the prognostic models was excellent. The 70-gene signature is an independent prognostic factor for LRR. A significantly lower local recurrence risk was seen in patients with a low-risk 70-gene signature compared to those with high-risk 70-gene signature.

Very low local recurrence rates after breast-conserving therapy: analysis of 8485 patients treated over a 28-year period

“…In addition, as an alternative to whole breast irradiation partial breast irradiation is currently studied, since most of the local recurrences occur at or near the tumor bed [42]. Further, in decision making for the use of RT the biological background of breast cancer may play a role [43].…”

Biomarkers of Tumour Radiosensitivity and Predicting Benefit from Radiotherapy

“…In the mastectomy group, the signature was evaluated separately in patients treated with and without post-mastectomy radiotherapy (PMRT). Those treated with PMRT and classified as high risk experienced more LRR at 10 years (LRR 11.0% high risk versus 3.1% low risk, P ¼ 0.004), whereas in patients who did not receive PMRT, classification as high or low risk did not affect LRR (LRR 12.9% high risk versus 9.2% low risk, P ¼ 0.302) [31]. Although the signature was predictive of LRR exclusively in radiotherapy treated patients in the mastectomy subgroup, high-risk classification by MammaPrint Ò was also shown to be an independent prognostic factor for LRR in the entire cohort and has already been proven to identify patients at high risk of distant metastasis [21].…”

Lessons Learned in Breast-Conserving Therapy

“…57,58 Speer and colleagues 59 developed a molecular signature for radiation response in breast cancer that is enriched for biologic concepts implicated in response to radiation therapy, including DNA damage repair and cell cycle regulation. They suggested that their signature outperforms previous signatures and may more accurately stratify the likelihood of local recurrence of breast cancer.…”